Chemotherapy will be attempted for several genetic disorders of the sphingolipid hydrolases, in particular Gaucher disease and metachromatic leukodystrophy. The sphingolipidoses can be characterized by neurological degeneration, accumulation of sphingolipids in the tissues, mental retardation, degeneration of the long bones, severe pain, blindness, circulatory blockage due to organ swelling, and other symptoms. My plan is to block the accumulation of the affected sphingolipid by slowing its rate of synthesis, to match the activity of the defective - but functioning - hydrolase. The hydrolases will then be able to maintain turnover without net accumulation. I believe that many of the pathological symptoms will be alleviated as the stored lipids enter the normal metabolic pathways. This will be done by two approaches: (1) inhibition of the synthetic enzyme by administration of specific inhibitors or (2) stimulation of enzyme pathways that compete with the lipid-synthesizing enzyme for substrate. In the former case, compounds will be tested in normal mice using inhibitors that we have developed by in vitro assay of the enzyme which makes glucocerebroside. This should produce depressed levels of the sphingolipid and have potential use in Gaucher disease. In the latter case, slowing of cerebroside sulfate synthesis will be attempted by feeding normal mice (a) readily sulfated phenols, (b) a low-sulfur diet, (c) and/or known inhibitors of taurine transport. These approaches should deplete the body of sulfur-containing amino acids, which provide sulfate ions for the synthesis of the sulfosphingolipid. The approach may be helpful for patients with metachromatic leukodystrophy. Additional potential inhibitors will be synthesized for blocking the enzymes which form glucocerebroside, ceramide (for Farber's disease), and sphingomyelin (for Niemann-Pick disease). They will be tested first with in vitro assays, then with mice as above.